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Regulatory Pathways for Registration of

Seasonal and Pandemic Influenza

Vaccines:

FDA Approach

6th Meeting with International Partners on Prospects for Influenza Vaccine Technology Transfer to Developing Country Vaccine Manufacturers

19 March 2013

David Cho, PhD, MPHSenior Scientist for Seasonal and Pandemic Influenza

Center for Biologics Evaluation and Research (CBER)

U.S. Food and Drug Administration

Department of Health and Human Services

2

FDA Overview

Office of the Commissioner

National Center for Toxicological Research

Center for DrugEvaluation and Research

Center for Biologics Evaluation and Research

Center for Tobacco Products

Center for Food SafetyAnd Applied Nutrition

Center for VeterinaryMedicine

Center for Devices andRadiological Health

Office of Regulatory Affairs

Office of FoodsOffice of Medical Products

and TobaccoOffice of Global Regulatory

Operations and Policy

3

CBER Overview

Office of the DirectorKaren Midthun, M.D., Director

Office of Blood Research and Review

Office of Biostatistics and Epidemiology

Office of Communications, Outreach and Development

Office of Cellular, Tissue and Gene Therapies

Office of Management

Office of Vaccines Research and Review

Office of Compliance and Biologics Quality

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Stages of Review and RegulationClinical Investigational Plan

Phase 1SafetyImmuno-genicity(prelim)

Phase 2Immuno-genicitySafetyDose Ranging

Phase 3EfficacySafetyImmuno-genicity

BLAData to support licensure;Inspection;Advisory Committee

Phase 4InspectionSafetyEfficacyLot Release

BLA SupplementPost-licensureChanges:New IndicationsDosingManufactureEquip./Facilities

IND

IND = Investigational New Drug Application;

BLA= Biologics License Application

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IND Role in Biologics

Approval Process� Mechanism and process to collect clinical data to

support the license application

�Demonstrate safety and efficacy

� Information for the package insert

� Chemistry, manufacturing, and controls (CMC)

�General biological product standards

�Process validation

� Assay validation

� Immunogenicity/activity

�Product quality control, lot release

� Stability data

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Biologics License Application (BLA)

� BLA is a marketing application

� Purpose is provide adequate information to allow FDA reviewers to reach a decision

�Biological product is safe and effective for its proposed use

�Proposed benefits outweigh risks

�Labeling is adequate

�Manufacturing and control methods are adequate

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U.S.-licensed Seasonal

Influenza Vaccines

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Seasonal Influenza Vaccine Licensure Pathways:

Biologics License Application (BLA)• “Traditional” Approval

– 21 CFR 601 Subpart A and C

• Approval “…based on data… which demonstrate that the manufactured product meets prescribed requirements of safety, purity and potency…”

• Accelerated Approval

– 21 CFR 601 Subpart E

• Approval “…on the basis of adequate and well-controlled clinical trials establishing that the product has an effect on a surrogate endpoint …reasonably likely…to predict clinical benefit…”

• Approval “..subject to the requirement that the applicant study the biological product further to verify and describe its clinical benefit…”

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Accelerated Approval for Inactivated

Influenza Vaccines

• FDA considers influenza vaccines to be in short supply

• CBER will consider anti-HA antibody levels (measured by the hemagglutination inhibition assay) as a likely surrogate marker for efficacy

• Accelerated approval can be sought based on immunogenicity provided:

– validated assays

– post-approval studies of clinical efficacy

– complete manufacturing data, controls & inspections

– satisfactory safety data; clinical trials and data from experience with same vaccine under foreign licensure can be supportive

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U.S.-licensed Seasonal Influenza VaccinesInactivated, intramuscular• Fluzone Sanofi Pasteur (> 6 months)• Fluzone High Dose* Sanofi Pasteur (> 65 years)• Fluvirin Novartis (> 4 years)• Fluarix* GSK (> 3 years) • FluLaval* IDB-GSK (> 18 years)• Afluria* CSL (> 5 years)• Agriflu* Novartis (> 18 years)

Inactivated, intradermal• Fluzone Intradermal Sanofi Pasteur (18-64 years)

Live Attenuated, intranasal• FluMist MedImmune (2-49years)

*-accelerated approval

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Recent Influenza Vaccine Approvals

• FluMist Quadrivalent– MedImmune, LLC

– February 29, 2012

• First licensed quadrivalent vaccine to prevent seasonal influenza

• For use in persons ages 2 years through 49 years

• Contains four strains of the influenza virus, two influenza A strains (H1N1 and H3N2) and two influenza B strains (Yamagata and Victoria lineages)

• Flucelvax – Novartis Vaccines and Diagnostics, Inc.

– November 20, 2012

• Trivalent vaccine

• First licensed seasonal influenza vaccine manufactured using cell culture technology (MDCK)

• For use in persons ages 18 years and older

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Recent Influenza Vaccine Approvals – Cont.

• Fluarix Quadrivalent– GlaxoSmithKline Biologicals

– December 14, 2012

• First licensed quadrivalent inactivated vaccine to prevent seasonal influenza

• For use in persons ages 3 years and older

• Contains four strains of the influenza virus, two influenza A strains (H1N1 and H3N2) and two influenza B strains (Yamagata and Victoria lineages)

• Flublok– Protein Sciences Corporation

– January 16, 2013

• Trivalent vaccine

• First licensed influenza vaccine manufactured using an insect virus (baculovirus) expression system and recombinant DNA technology

• For use in persons ages 18 through 49

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U.S.-licensed Seasonal Influenza Vaccines: Routine Licensing Actions

• Each year, one or more of the vaccine strains may be replaced with a new strain.

• Each year, submission of a prior approval manufacturing supplement to an existing biologics license application (BLA) is required for annual influenza strain change.

– “Strain change supplement”

• Clinical Data

– Inactivated vaccines: No clinical data

– Live attenuated: Limited clinical data

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WHO recommendations for Influenza Vaccine Composition

Northern Hemisphere: 2013-2014

• Recommended that the following viruses be used for influenza vaccines in the 2013-2014 influenza season (NH winter):– An A/California/7/2009 (H1N1) pdm09 – like virus

– A(H3N2) virus antigenically like the cell-propagated prototype virus A/Victoria/361/2011

– B/Massachusetts/2/2012-like virus (B/Yamagata lineage)

• It is recommended that quadrivalent vaccines containing two influenza B viruses contain the above three viruses and a B/Brisbane/60/2008-like virus (B/Victoria/2/87 lineage vaccine virus)

• As in previous years, national or regional control authorities approve the composition and formulation of vaccines used in each country

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CBER is a WHO Essential Regulatory Laboratory (ERL): Influenza product quality laboratories

• CBER’s ERL activities include:

1. Yearly Strain Selection

– Antigenic characterization of circulating influenza isolates for strain selection purposes

2. Generation of high-growth reassortant viruses (reference strains) suitable for use in vaccine production

3. Production, calibration (cross-calibration) and provision of SRID reference reagents to measure vaccine potency

4. Antigenic confirmation of production seeds

5. Lot Release including potency testing

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Influenza Vaccine TimetableSteps JAN FEB MAR APR MAY JUN JUL AUG SEP OCT NOV DEC

Surveillance*

Select Strains*

Reassortants*

Reagents*

Production*

Release*

Distribution

Administer

Post market*

Seasonal vaccine

* - FDA involvement

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U.S.-licensed Pandemic

Influenza Vaccines

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Selected Influenza A (H1N1) Events

April 21: CDC Report - 2 Cases of Illness Due to Influenza A (H1N1) Virus

June 11: WHO Phase 6 Pandemic Declared

July/August: Pilot Vaccines Available for Testing

July 23: VRBPAC on H1N1 Vaccine Regulatory Approach and Clinical Studies

2009 April May June July August September

May 19: > 9,000 Cases of H1N1 Disease in 40 Countries (79 deaths)

September 15: FDA Approves Four H1N1 Vaccines

April 26: DHHS Acting Sec: Public Health Emergency

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Influenza A (H1N1) 2009 Vaccines

• Approved as strain change supplements to the seasonal

influenza virus vaccine BLAs

• Consistent with licensure of annual strain changes to

seasonal vaccines

• Consistent with past regulatory actions

– 1986 - Influenza A/Taiwan/1/86 H1N1

– Supplemental monovalent vaccines licensed as

strain change supplements

– No clinical data

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Influenza A (H1N1) 2009 Vaccines:Strain Change Supplements

• Manufacturers utilized same egg based manufacturing

process as for their licensed seasonal vaccines

• Vaccines contained the same quantity of antigen as a

single strain of seasonal vaccine

• Same population usage as the licensed seasonal

vaccine

• Same clinical data requirements as for seasonal

influenza vaccine strain change supplements

� Inactivated vaccines: No clinical data

�Live attenuated: Limited clinical data

• However, clinical data obtained to verify approach (e.g.,

dose and dosing regimen)

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Influenza Vaccine TimetableSteps JAN FEB MAR APR MAY JUN JUL AUG SEP OCT NOV DEC

Surveillance*

Select Strains*

Reassortants*

Reagents*

Production*

Release*

Distribution

Administer

Clinical Studies

Seasonal vaccine Pandemic vaccine (2009)

* - FDA involvement

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Influenza A (H1N1) 2009 Vaccine

Strain Change Supplements

• Approval: September 15, 2009

– Sanofi pasteur

– Novartis

– CSL

– MedImmune (LAIV)

• Approval: November 10, 2009

– IDBiomedical/GSK

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Influenza A (H1N1) 2009 Vaccines

• Licensed for use in the same populations as

each manufacturer’s seasonal influenza vaccine:

– Sanofi pasteur > 6 months of age

– Novartis > 4 years of age

– CSL >18 years of age (>6m Nov. 10)

– IDB/GSK >18 years of age

– MedImmune 2-49 years of age

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Pandemic Vaccine – Challenges

• Regulatory:– Pathways and regulatory processes to speed vaccine availability

– Assuring safety and public confidence

– Facilitating vaccine manufacturing and availability

• Manufacturing:– Seed virus development

– Potency testing reagents

• Clinical data:– Antigen dose

– Number of doses

– Antigen sparing: use of oil–in-water adjuvants

– Timing of availability of clinical data

• Public health: – Vaccine use – Distribution– Assuring safety and public confidence

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Expediting Influenza Vaccine Availability:

Collaborative work underway

• Develop and optimize high yielding and highly immunogenic vaccine reference strains

• Develop alternatives for rapid preparation and calibration of vaccine reagent standards

• Work towards standardization of current SRID potency assay– Could include the use of harmonized global reagents

• Develop new potency assays with improved accuracy and sensitivity– Some assays might not require new reagent production

• Accelerate sterility release testing from current 14 days – Proposed Rule to amend the sterility test requirements for

biological products (June 21, 2011)– Possible faster availability of vaccine during pandemic or

emergency

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Pandemic Vaccines: International Collaborations

• Existing relationships/activities key to success regarding

pandemic

– Confidentiality agreements with a number of regulatory agencies

• Worldwide communications/collaborations

– Global dialogue facilitated by WHO

– Dedicated routine and on-going confidential regulatory discussions with foreign counterparts

– Seed virus development

– Potency testing reagents

– Technical assistance to developing countries via WHO

– CBER agreed to be Reference NRA for WHO vaccine prequalification for multiple H1N1 vaccines

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Preparing for the Next Pandemic

Based on Experience with

2009 H1N1 Vaccines

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Preparing for the Next Pandemic

• Regulatory pathways defined before the pandemic

�Unadjuvanted (seasonal influenza manufacturer)

� New subtype: BLA (e.g. Sanofi Pasteur’s Influenza Virus Vaccine, H5N1)

� Subtype in seasonal: Strain change supplement to seasonal (e.g. Influenza A (H1N1) 2009 monovalent vaccines)

�Adjuvanted (seasonal influenza manufacturer)

� No U.S-licensed seasonal

• Preliminary immunogenicity data (+/- adjuvant) with subtypes of pandemic potential before a pandemic

�Clinical studies with the pandemic strain vaccine will likely be needed to verify dose and dosing regimen

� Develop a concept protocol

• Develop plans for post-marketing safety surveillance

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• Vaccine availability

– Explore options to make vaccine available sooner• Alternative manufacturing technologies/platforms (e.g.,

cell-based or recombinant vaccines)

– Progress in developing a correlate of protection

• Reagents/potency testing

– Develop alternatives to SRID

• Expect manufacturing challenges

– Experienced manufacturers likely have knowledge and capacity to address these challenges

• Yield

• Potency testing reagents

– Stability – collect data with monovalents

Preparing for the Next Pandemic (con’t)

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• Public health

– Assuring safety and public confidence

• Effectively communicate severity of pandemic

and the uncertainty of predictions

• Effectively communicate manufacturing issues

and the impact on supply

– Build on the surveillance systems developed and

used in 2009 H1N1 pandemic

• International collaboration (WHO, regulatory and

public health agencies, etc.) essential

Preparing for the Next Pandemic (con’t)

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EUA of Medical Products

• The Secretary of DHHS can authorize use of medical

products in a declared emergency under an Emergency

Use Authorization (EUA).

• This ability has been delegated to the FDA Commissioner.

• During a pandemic emergency in the U.S., the FDA

Commissioner may authorize:

– Use of an unapproved product

– Unapproved use of an approved product if the statutory criteria for issuance of an EUA are met.

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Summary

• In the U.S. experience, influenza vaccines have a long track record of safety and effectiveness

• A strong post-marketing safety evaluation system is important, both for seasonal and pandemic vaccines, and for older as well as newly introduced influenza vaccines

• Seasonal influenza vaccine manufacturing capacity and experience form an important basis for pandemic response

• Influenza pandemics will continue to challenge public health officials globally to make critical decisions about vaccine approval, use and distribution

• National regulatory authorities must be prepared to respond with regulatory pathways to expedite the availability of vaccines

• Novel vaccine approaches may provide important alternatives (e.g., cell-based and recombinant manufacturing technologies, novel adjuvants and delivery systems)

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FDA guidance documents on seasonal and pandemic influenza vaccines

• http://www.fda.gov/BiologicsBloodVaccines/Guid

anceComplianceRegulatoryInformation/Guidanc

es/Vaccines/ucm074794.htm

• http://www.fda.gov/BiologicsBloodVaccines/Guid

anceComplianceRegulatoryInformation/Guidanc

es/Vaccines/ucm074786.htm

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Foreign Regulatory Seminar (Web-based): CBER’s Regulation of Biologics

• http://www.fda.gov/BiologicsBloodVaccines/Inter

nationalActivities/ucm272086.htm

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Acknowledgements

• CBER & FDA colleagues

• DHHS partners

CBER vaccines website: http://www.fda.gov/BiologicsBloodVaccines/default.htm

HHS influenza website: www.flu.gov

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www.fda.gov